AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells.
AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells.
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尽管在治疗乳腺癌方面取得了重大进展，特别是通过使用靶向治疗，但复发和化疗耐药性仍然是最大限度地减少疾病负担的主要障碍。越来越清楚的是，一种称为癌症干细胞（CSC）的罕见细胞亚群，能够通过上皮向间充质转化（EMT）产生，并能够引发肿瘤和自我更新，有助于治疗抗性和转移。这意味着更有效的治疗应该靶向化学抗性CSC和产生它们的增殖上皮细胞，以逆转EMT并减弱它们向CSC的转化。在这里，我们证明了一种新的功能，AXL在上游作用，诱导EMT在正常和永生化的人乳腺上皮细胞中的一个明显的正反馈回路机制，并调节乳腺CSC（BCSC）的自我更新和化疗耐药性。使用MP470（amuvatinib）下调AXL逆转了间充质正常人乳腺上皮细胞和鼠BCSC中的EMT，减弱了BCSC的自我更新并恢复了BCSC的化学敏感性。AXL的表达还与干细胞基因的表达、转移基因的调节、致瘤性的增加有关，并且对于BCSC的侵袭和迁移是重要的。AXL的失活还导致NFκB通路的下调，减少体内肿瘤形成。总之，我们的数据表明，针对AXL的靶向治疗与全身治疗相结合，有可能改善对抗癌治疗的反应，并减少乳腺癌复发和转移。
Despite significant progress in the treatment of breast cancer particularly through the use of targeted therapy, relapse and chemo-resistance remain a major hindrance to the fight to minimize the burden of the disease. It is becoming increasingly clear that a rare subpopulation of cells known as cancer stem cells (CSC), able to be generated through epithelial to mesenchymal transition (EMT) and capable of tumor initiation and self-renewal, contributes to treatment resistance and metastases. This means that a more effective therapy should target both the chemoresistant CSCs and the proliferating epithelial cells that give rise to them in order to reverse EMT and attenuate their conversion to CSCs. Here, we demonstrate a novel function of AXL in acting upstream to induce EMT in normal and immortalized human mammary epithelial cells in an apparent positive feedback loop mechanism and regulate breast CSC (BCSC) self-renewal and chemoresistance. Downregulation of AXL using MP470 (amuvatinib) reversed EMT in mesenchymal normal human mammary epithelial cells and murine BCSCs attenuating self-renewal and restored chemosensitivity of the BCSCs. AXL expression was also found to be associated with expression of stem cell genes, regulation of metastases genes, increased tumorigenicity, and was important for BCSC invasion and migration. Inactivation of AXL also led to downregulation of NFκB pathway and reduced tumor formation in vivo. Together, our data suggest that targeted therapy against AXL, in combination with systemic therapies, has the potential to improve response to anti-cancer therapies and to reduce breast cancer recurrence and metastases.
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DOI：
10.2741/3782
发表时间：
2011-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Chen W;Li Z;Bai L;Lin Y
通讯作者：
Lin Y
影响因子：
3.8
作者：
Qi W;Cooke LS;Stejskal A;Riley C;Croce KD;Saldanha JW;Bearss D;Mahadevan D
通讯作者：
Mahadevan D
DOI：
10.1186/bcr2106
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Grimshaw MJ;Cooper L;Papazisis K;Coleman JA;Bohnenkamp HR;Chiapero-Stanke L;Taylor-Papadimitriou J;Burchell JM
通讯作者：
Burchell JM
影响因子：
4
作者：
Nakano, T;Tani, M;Yokota, J
通讯作者：
Yokota, J
影响因子：
3.1
作者：
Chung, BI;Malkowicz, SB;McGarvey, TW
通讯作者：
McGarvey, TW